Open AccessViolacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activity
Author(s) -
Tatyana Almeida Tavella,
Noeli Soares Melo da Silva,
Natalie J. Spillman,
Ana Carolina Andrade Vitor Kayano,
Gustavo Capatti Cassiano,
Adrielle A. Vasconcelos,
Antônio Pedro Camargo,
Djane Clarys Baía da Silva,
Diana Fontinha,
Luis Carlos Salazar Alvarez,
Letícia Tiburcio Ferreira,
Kaira Cristina Peralis Tomaz,
Bruno J. Neves,
Ludimila Dias Almeida,
Daniel Youssef Bargieri,
Marcus Vinícius Guimarães Lacerda,
Pedro Cravo,
Per Sunnerhagen,
Miguel Prudêncio,
Carolina Horta Andrade,
Stefanie Costa Pinto Lopes,
Marcelo Falsarella Carazzolle,
Leann Tilley,
Elizabeth Bilsland,
Júlio César Borges,
Fábio Trindade Maranhão Costa
Publication year - 2021
Publication title -
acs infectious diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.324
H-Index - 39
ISSN - 2373-8227
DOI - 10.1021/acsinfecdis.0c00454
Subject(s) - proteostasis , chaperone (clinical) , plasmodium falciparum , biology , proteasome , chemical chaperone , unfolded protein response , drug discovery , microbiology and biotechnology , malaria , biochemistry , endoplasmic reticulum , immunology , medicine , pathology
Antimalarial drugs with novel modes of action and wide therapeutic potential are needed to pave the way for malaria eradication. Violacein is a natural compound known for its biological activity against cancer cells and several pathogens, including the malaria parasite, Plasmodium falciparum (Pf). Herein, using chemical genomic profiling (CGP), we found that violacein affects protein homeostasis. Mechanistically, violacein binds Pf chaperones, Pf Hsp90 and Pf Hsp70-1, compromising the latter's ATPase and chaperone activities. Additionally, violacein-treated parasites exhibited increased protein unfolding and proteasomal degradation. The uncoupling of the parasite stress response reflects the multistage growth inhibitory effect promoted by violacein. Despite evidence of proteotoxic stress, violacein did not inhibit global protein synthesis via UPR activation-a process that is highly dependent on chaperones, in agreement with the notion of a violacein-induced proteostasis collapse. Our data highlight the importance of a functioning chaperone-proteasome system for parasite development and differentiation. Thus, a violacein-like small molecule might provide a good scaffold for development of a novel probe for examining the molecular chaperone network and/or antiplasmodial drug design.